A Primer On Biopharma Manufacturing From Bristol-Myers Squibb's Lou Schmukler

By Rob Wright, Chief Editor, Life Science Leader
Follow Me On Twitter @RfwrightLSL

When Lou Schmukler arrived at Bristol-Myers Squibb (BMS) in 2011, the company’s best-selling drug was Plavix, a small molecule drug used to prevent heart attacks and strokes in persons with heart disease. If you look up a list of best-selling drugs of all time, you will likely see Plavix ranked near the top. Today however, the president of Global Product Development and Supply at BMS would tell you the company’s best-selling products include a portfolio of major large molecule drugs.  These include the immuno-oncology agents Opdivo, Yervoy and Empliciti, used to treat certain types of cancers, and Orencia, for treatment of rheumatoid arthritis. In an upcoming feature in Life Science Leader, we explore Schmukler’s charge of shifting BMS’s product development and manufacturing operations over from that of a pure Big Pharma focused on small molecule primary care medicines to one more aligned with being a specialty drug company which further enabled  BMS’ bold overall strategy.. But I was curious regarding the balancing act such a move required, because Plavix (a partnered product with Sanofi) generated lifetime revenues in excess of $82 billion, and it is not like you can just focus on the future without properly managing the present. What follows is a Q&A with Schmukler around some of the differences around the manufacture of small molecule and large molecule products.

Discuss your approach to maintaining manufacturing supply/operations for a small molecule blockbuster still on patent, while building for the future launch of a blockbuster biologic.

Given the dual nature of our strategy for biologics and pharmaceuticals, we initially created what we termed two integrated end-to-end (E2E) operating units, one for large molecule and the other for small molecule. This helped ensure the right focus and resource allocation. We were able to do this because (with minor exceptions) sites had dedicated missions across the two technology platforms. We were fortunate in this regard as many large organizations don’t have this “clean” split. Later we also created an established brands operating unit (EBO) to define and advance a segmentation, differential investment strategy to ensure the best respective resource allocation, investment program and metrics and targets for our key and innovation portfolio versus the legacy late-life cycle portfolio.

Any effective operations organization is always challenged with the task of executing today (i.e., for the legacy small molecule portfolio) as well as preparing for the future (i.e., the new biologic blockbuster). You need the right focus on talent and facilities to do both well, and pre-invest for future growth irrespective of product modality, leveraging internal and external capabilities. Operations organization must deliver high-quality medicines to patients around the world right the first time — and every time.

Discuss some of the specific manufacturing challenges/risks/differences presented when comparing the processes of Opdivo to something like Plavix.

• A biologic is manufactured in a living system such as a microorganism, plant or animal cells. Most biologics are very large, complex molecules, or mixtures of molecules. Many biologics are produced using recombinant DNA technology.

• A small molecule drug is typically manufactured through chemical synthesis, which means that it is made by combining specific chemical ingredients in a sequenced process.

• Small molecule drugs generally have well-defined chemical structures, and a finished small molecule drug can usually be analyzed to determine all its various components. By contrast, it is difficult, and sometimes impossible, to characterize a complex biologic by testing methods available in the laboratory, and some of the components of a finished biologic may be unknown.

• For biologics, "the product is the process." Because the finished product cannot be fully characterized in the laboratory, manufacturers must ensure product consistency, quality, and purity by ensuring that the manufacturing process remains substantially the same over time. By contrast, a small molecule drug manufacturer can change the manufacturing process extensively and analyze the finished product to establish that it is the same as before the manufacturing change.

• The living systems used to produce biologics can be sensitive to very minor changes in the manufacturing process. Small process differences can significantly affect the nature of the finished biologic and, most importantly, the way it functions in the body. To ensure that a manufacturing process remains the same over time, biologics manufacturers must tightly control the source and nature of starting materials, and consistently employ a myriad of process controls that assure predictable manufacturing outcomes.

• The approximately 500-fold difference in molecular weight of these compounds leads to a corresponding increase in complexity. The chemical processing technology to produce small molecule drugs is more advanced and established as its been developed over many decades. Production of biologics is relatively new, by contrast, and requires technology for aseptic production in living cells, sterile fill-finish drug product manufacturing, and cold chain management. Most small molecule drugs are stable at ambient temperatures and orally available, while most biologics are temperature-sensitive and administered parenterally. This requires a very advanced state of environmentally-controlled production, shipping, and quality control. While many fundamental manufacturing principles are certainly shared, the unique aspects of the two product classes do require asset-specific investment in facilities and infrastructure, staff training and expertise, and regulatory and quality oversight. Also, the cost of manufacturing a biologic is significantly greater than small molecules.

Lastly, I want to mention that sales of our small molecule products (i.e., Eliquis) are significant. BMS discovers and develops products focused on unmet patient needs in very specific therapeutic categories (i.e., oncology, immunology, cardio-pulmonary, and fibrotic diseases) and is focused on the outcomes, regardless of manufacturing modality. Therefore, we produce using our internal assets when we have capability and capacity, and at other times, we leverage external partners or CDMOs for product development and manufacture.

Explain the different employee skillsets required for small molecules versus biologics.

For both the production of synthetic small molecules and biologics, chemical engineering expertise and capability is a necessity. For small molecules, synthetic organic chemistry and physical chemistry capabilities are required. Biologics, on the other hand, require staff with expertise in biology, biochemistry, and microbiology. Staff with analytical chemistry expertise are required to develop and maintain BMS quality-control systems, but the structural complexity of biologics requires significantly more investment in, for instance, analytical biochemistry, mass spectrometry, and bioassay development. With the advanced state of facility integration, analytics, and automation, we are also increasingly reliant on staff with computer science, statistics and process-automation expertise.